Schizophrenia: More dopamine, more D 2 receptors

Schizophrenia is a major therapeutic challenge of modern medicine, and one of the last frontiers of brain research. The illness is defined by delusions, hallucinations, disorganized behavior, and cognitive difficulties such as memory loss. It occurs in ≈1% of the world population and usually first appears in early adulthood. Although antipsychotic medications have dramatically improved the lives of patients with schizophrenia, the causes of the illness remain unknown. Of the many contemporary theories of schizophrenia, the most enduring has been the dopamine hypothesis. As originally put by Van Rossum in 1967 (ref. 1, p. 321), “When the hypothesis of dopamine blockade by neuroleptic agents can be further substantiated, it may have fargoing consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could be part of the aetiology … emphasis added.” Indeed, this speculative sentence by Van Rossum foreshadows the title of the important work by Abi-Dargham et al . (2) in this issue of PNAS: “Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.” The discovery of the antipsychotic/dopamine receptor (3, 4), now commonly known as the dopamine D2 receptor, led to repeated confirmation that it is the primary site of action for all antipsychotics (3–5), including clozapine and quetiapine (6). All these drugs have different potencies at the receptor. The potency depends on the drug's dissociation constant at D2, which, in turn, relates to the rate of release of the drug from the D2 receptor. For example, the dopamine D2 receptor releases clozapine and quetiapine more rapidly than it does any of the other antipsychotic drugs (7, 8). Given the tight correlation between the clinical potency and the D2-blocking action of the antipsychotic medications, dopamine overactivity could be the common denominator in the …